Mechanism of a arsenic-mediated cancer development

全世界有超过1000万人饮用高浓度砷（>5 mg/l）的水。据报道，在流行病学研究中，人类发生皮肤癌、肺癌、肝癌或膀胱癌的风险增加。这些报告表明，砷是人类的致癌物质。为了防止饮用砷污染水的人群中癌症的爆炸性增加，我们需要阐明砷诱发癌症的机制以建立有效的治疗方法。c-RET原癌基因编码一种受体型酪氨酸。c-RET的配体是胶质细胞源性神经营养因子（glial cell line-derived neurotrophic factor，GDNF），其信号传导在肾器官发生和肠神经发生中起重要作用。Ret激酶通过点突变或基因重排激活。c-RET原癌基因的生殖系突变与多发性内分泌腺瘤2A型（MEN 2A）的发生相关。本研究通过分析砷对RET酪氨酸激酶的激活作用，阐明砷对肿瘤发生的作用机制：1）砷对RET-MEN 2A酪氨酸激酶的超激活作用：砷促进c-RET原癌基因产物（c-RET蛋白酪氨酸激酶）的活性。砷可激活RET癌基因产物（RET-MEN 2A：c-RET，半胱氨酸634取代精氨酸）的激酶活性，其活性可因基因突变而增加3-10倍; 2）砷可促进c-RET中关键酪氨酸的自磷酸化，酪氨酸905和1062的自磷酸化对c-RET激酶的激活至关重要。砷促进c-RET中905和1062酪氨酸的自磷酸化。3）SOD 1（超氧化物歧化酶1）对砷介导的RET激酶激活的影响。

More than ten million people in the world suffered drinking water with high concentration of arsenic (>5 mg/1). It is reported that a risk of cancer development in skin, lung, liver or bladder increases in human in epidemiological research. These reports suggest that arsenic is a carcinogen in the human. To prevent against an explosive increase of cancer in the people who drink arsenic-polluted water, we need to clarify the mechanism of arsenic-induced cancer for establishing effective therapies.The c-RET proto-oncogene encodes a receptor type tyrosine. Ligand of c-RET is glial cell line-derived neurotrophic factor (GDNF), and its signaling is essential for renal organogenesis and enteric neurogenesis. The Ret kinase is activated by point mutations or gene rearrangement. Germ line mutations of the c-RET proto-oncogene are associated with the development of multiple endocrine neoplasia type 2A (MEN2A). Enhancement of oncogenic RET activity through autophosphorylation of tyrosine 905 and tyrosine 1062 are crucially important for transformation.In this study, we clarified mechanism of arsenic-mediated cancer development through analysis of RET tyrosine kinase activation.1) Arsenic-mediated superactivation of RET-MEN2A tyrosine kinase.Arsenic promotes c-RET proto-oncogene product activity (c-RET protein tyrosine kinase). Arsenic superactivates kinase activity of RET oncogene product (RET-MEN2A: c-RET with cysteine 634 replaced arginine), in which kinase activity was 3-10 fold augmented by genetic mutation.2) Arsenic promoted autophosphorylation of key tyrosines for activation in c-RET.Autophosphorylation of tyrosines 905 and 1062 were reported to be crucially important for c-RET kinase activation. Arsenic promoted autophosphorylation of 905 and 1062 tyrosines in c-RET.3) Effect of SOD1 (superoxide dismutase 1) on arsenic-mediated RET kinase activation.We showed that SOD1 inhibited UV-mediated but not arsenic-mediated RET tyrosine kinase activity.